Our aim is to develop of a new type of imaging "macroscope" that performs ultra-deep (several millimeters) fluorescence imaging in thick tissue while providing out-of-focus background rejection. Our proposed method for out-of-focus blur rejection is based on a novel technique called Dynamic Speckle Illumination (DSI) microscopy that was recently invented in our lab. Our goal is to build a portable DSI macroscope and establish its potential for in-vivo molecular-imaging applications such as cancer research and diagnosis, as well as small animal imaging and surgery. DSI microscopy consists of a simple modification to a standard widefield fluorescence microscope. Sample illumination is performed with random laser speckle patterns rather than with a lamp. The main advantage of DSI microscopy is that it provides depth discrimination and out-of-focus blur reduction in thick tissues without the use of a complicated scanning mechanism. We have developed the full theory of DSI microscopy and already demonstrated sub-micron-resolution imaging with confocal-like background rejection of GFP-labeled neurons, down to about 100[unreadable]m in mice brain. We propose to develop a new instrument that performs much deeper imaging but with lower resolution. Our targeted depth is several millimeters, down to perhaps a centimeter. To attain this goal we propose to significantly re-design of our DSI microscope to incorporate a long working-distance telecentric objective, near-infrared laser illumination, and a more sensitive CCD camera. We also plan to combine DSI with structured illumination contrast and multipsectral imaging (for the latter, we will work with Cambridge Research & Instrumentation). The defining advantage of our DSI macroscope compared to conventional commercially available macroscopes will be that DSI provides out-of-focus background rejection, enabling significantly better localization and visualization of labeled structures within thick tissue. Initial testing of our DSI prototype will be performed on tissue phantoms provided by a radiology lab. Widefield fluorescence macroscopy with out-of-focus blur rejection. Public health: We propose to develop a simple and inexpensive device that performs ultra-deep fluorescence imaging with out-of-focus blur rejection, for small animal cancer-model imaging. Our goal is to build a new tool for cancer research that can eventually be implemented in the clinic. [unreadable] [unreadable] [unreadable]